UA44221C2 - ADENOSINE DERIVATIVES, METHOD OF OBTAINING THEM, PHARMACEUTICAL COMPOSITION BASED ON THEM, METHOD OF OBTAINING PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The present invention relates to derivatives having the formula (I) as well as to addition salts thereof and their utilisation in therapeutics particularly as antalgic and antihypertensive agent.

Description

The present invention relates to derivatives of adenosine of the general formulas (I), presented below, as new compounds and, if possible, to their addition salts, in particular to pharmaceutically acceptable salts.

The proposed compounds have a very valuable pharmacological profile, as they have, on the one hand, in particular, analgesic properties, and on the other - antihypertensive properties.

The present invention further relates to the method of obtaining the specified products, to the synthesis of intermediate products and to the use of these products in therapy.

These derivatives of adenosine have the general formula (1):

Kz

E cha MN z 6 ri dk M

M

1 S

In I

(Thank you M Z

Kk in which - Vi is a hydrogen atom, a halogen atom, a lower alkyl radical, a lower O-alkyl radical, a lower o5-alkyl radical or a phenyl radical, and can be in 2-, 4-, 5-, 6- or 7-positioned indoles, - n - is an integer from 0 to 4, - Ag - is a lower alkyl radical, lower alkenyl radical, lower alkynyl radical, C3-C7-cycloalkyl radical or lower O-alkyl radical, - phenyl or naphthyl radical , unsubstituted or substituted by 1 to 4 identical or different substituents selected from the halogen atom, nitro, lower alkyl, lower O-alkyl or lower 5-alkyl groups! and group! -MA?N", Ah? and Kv are a hydrogen atom or a lower alkyl radical, and is a heterocyclic radical selected from pyridine and thiophene, unsubstituted or substituted by 1 to 4 identical or different substituents selected from a halogen atom, nitro, lower alkyl, lower O-alkyl or lower 5 -alkyl group, - or, in addition, when p is equal to 2, C or 4, the group -MAoN:io, He and Nio simultaneously represent a lower alkyl radical or form, together with the nitrogen atom to which they are attached, a heterocycle selected from morpholine , piperidine and pyrrolidine, - Vz and Ka, which are identical! or various, represented by a hydrogen atom or a lower alkyl radical, and - B5 is the group -MHNA1, Vi is a lower alkyl radical, a C3-C7-cycloalkyl radical or a lower alkyl chain possessing an alcohol or sulfur functional group, or, in addition , the group - (СНг)п - MA»Nno, p, Ve and Kio are more defined.

Derivatives according to the invention are mainly derived from formulas! (I), specified above, in which: - B is a hydrogen atom, a halogen atom, a lower alkyl radical, a lower O-alkyl radical, a lower o5-alkyl radical or a phenyl radical, and can be in the 2- or 5-position of indole , - n - is an integer equal to 0, 1 or 2, - Bg - is a lower alkyl radical, lower alkenyl radical, lower alkynyl radical, C3-C7-cycloalkyl radical or lower O-alkyl radical, - phenyl or naphthyl radical, unsubstituted or substituted by one to four identical or different substituents selected from the halogen atom, nitro, lower alkyl or lower O-alkyl groups and the group -"МА7Рв, А? and Kz are a hydrogen atom or a lower alkyl radical, - a heterocyclic radical selected from pyridine and thiophene, unsubstituted or substituted by a halogen atom, - mly, in addition, when n - 2, the group -MA»eNio, No and Kio are simultaneously lower alkyl radical or forms together with the nitrogen atom to which they are attached, a heterocycle selected from morpholine, piperidine and pyrrolidine - Vz and Ka, which is the same! or various, represented by a hydrogen atom or a lower alkyl radical, and - B5 is the group -МННА1, Vii is a lower alkyl radical, a C3-C7-cycloalkyl radical or a lower alkyl chain possessing an alcohol or sulfur group.

In the description and in the claims of the invention, a lower alkyl radical means a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is, for example, a methyl, zyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, isopentyl, hexyl or isohexene radical.

In the description and in the claims of the invention, a lower alkenyl radical is understood to mean a straight or branched hydrocarbon chain having from 1 to b carbon atoms and possessing a double bond, such as, for example, a shading radical, and a lower alkynyl radical is understood to be a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms and possessing a triple bond, such as, for example, the tin group.

The C3-C7-cycloallyl radical means a saturated cyclic radical, preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

Halogen means a chlorine, bromine, iodine or fluorine atom.

A lower alkyl chain having an alcohol functional group means a lower alkyl chain in which one of the hydrogen atoms is replaced by a hydroxyl group. Such a chain, for example, is a 1-hydroxy-3-methylpropan-2-yl chain.

Under the lower alkyl chain, which has a sulfur functional hydrogen atom, it is replaced by a lower one

O-alkyl group. Such a chain, for example, is a chain of 2-methoxystyl.

As for the therapeutic potential of adenosine itself, many derivatives of that nucleoside have been described! in the literature. The following work! can give instructions! as examples: - doshpatai oi Medisipa! Spettivigu 1973, mine. 16, Mo. 4, rows 358 - 64; - EN 2 154 527; - ER 0 267 878; - MO 88/03 148; - MO 88/03 147; - MO 86/00 310; - MO 92/05 177; - Viospetisa! Rnappasoiodu 1974, my. 23, rows 2283 - 89; - 5 4,167,565; - ER 0 232 813; - O5 5,023, 244.

Among the many works, there were instructions! in essence, only two derivatives with indole in the b-position of adenosine.

Thus: an article published in Choshigpai! oh Measipa! Spettivig, and patent EE 2 154 527, both describe the same product:

M-6-/2-(indol-3-yl)ztyl/adenosine (derivative A):

MN with Y and M

M M X no

M M

NOSNO on on

Производное А статья в Виоспетисай! RPpaptasoiud describes one derivative of 5-methoxytryptamine, which is also specified in document EC2154527 (derivative B):

SNO, oh don

M

M. M. Kh

What

M M nosno and he on

Derivative V

It can be noted that the article in the recent Medisipaya of Spitivig describes derivative A as possessing platelet aggregation inhibitory activity, while the French patent mentions actions on the central nervous system, blood circulation and heart without further clarification. Viospetisa! Rpappasoiodo determines that derivative B has antilipolytic activity.

It can be pointed out that in the described compounds, on the one hand, the indole derivative is never substituted at the indole nitrogen atom, and, on the other hand, the sugars at adenosine are not affected.

At the present time, the applicant discovered that surprisingly and unexpectedly, the substitution of the nitrogen atom of the indole ring together with the conversion of the primary sugar alcohol to the amide functional group gives products with a particularly valuable pharmacological profile, especially in the field of analgesics.

In one embodiment, Ni is a hydrogen atom.

In the second variant of HB; is a metal radical.

In another embodiment, Ni is a methoxyl radical.

In one embodiment, n is a number equal to 0.

In the second variant, n is an integer equal to 1.

In the second option, n is an integer equal to 2.

In one embodiment, Kg is a methoxyl radical.

In another variant, Ko" is a cyclopentane radical.

In another variant, Ko" is an isopropyl radical.

In the second variant, K" is a 2,5-dimethylphenyl radical.

In another variant, Ko is a piperidinyl radical.

In one embodiment, Kz is a hydrogen atom.

In one embodiment, Ka is a hydrogen atom.

In another variant, Ka is a metal radical.

In one embodiment, K5" is an M-cyclopropylamine radical.

Particularly preferred compounds according to the invention selected from derivative formulas oo

X z u o: i r i I o Y "MN

SNU s M -olo y a on (0)

MN

Y Y br o;

СНу in M - mol and g;

HE HE

MN

AI St

M

Yi Fe and;

About t

Hey oh a

HE HE

According to the invention, compounds of formula (I) can be synthesized! as follows:

Interaction of amine formulas! (Ii):

Kz

Ki

MN"

Ka

Eat what

Ko Formula (I) in which No, RN", Az and Ka and n determinations! above, with a 6-halopurine riboside of the formula (IP):

h

M

Her in; scha M

M

Ki2 o shka Formula (Ш)

KiIzO OK in which X is a halogen atom, preferably chlorine or bromine, Kig2 is a SOK group, H5 is more defined, or a CHogOH group, and Wiz and Aii are protective groups for an alcohol functional group, such as, for example, acetyl, benzoyl or benzyl , or may together form a second protecting group, for example a dioxolane structure, in a solvent such as, for example, an alcohol, or in an aprotic solvent such as dimethylformamide, in the presence of a base such as trisethylamine, pyridine, or sodium, potassium, or calcium carbonate, or , in addition, in the presence of two equivalent amine formulas! (II) at a temperature between 20" and 140"C will lead to the formation of a compound of the formula (IM):

VZ

Kk, uk hi and M

Y V; se M

TT M

KE; Ego

VISA OK Formula (TU) in which Ni, R», Nz, Va, Vi2, Visa, Via and other definitions! more

If the indoleamine derivative of the formulas (III) has a center of asymmetry, the compounds should be considered either in the racemic formula or in the optically active form. If it is desirable to obtain an optically active derivative, attention will be paid to the separation of stereoisomers at the indoleamine stage, before the connection with b-halopurine ribosides of the formulas! ( II), by ordinary methods of separation of optical isomers known to specialists, for example, by recrystallization of salts formed with optically active tartrates. After the separation of optically active tartrates, the optically active base, released from it by tartaric acid!, will bind to b-halopurine ribosides of the formula (PP ).

In that case, when the Ki" radical is a CH2OH group, it can be oxidized by chromium trioxide in the following way:

E..ZSMIOT apa N.O.ERIT2, Spet.Veg. 1970, 103, 1867, or with potassium permanganate according to the method described:

R.O.NARERERE apa A.NAMRTOM, .Ogd.Spet. 1970, 35, p. 5, 1688, the obtained ribouronic acid is then converted into an acid chloride by interaction, for example, with thionyl chloride, and then into an amide by interaction with an amine by methods known to specialists. Removal of the protective group from secondary alcohols OKiz and OKia can be carried out in different ways, for example, in a basic medium, such as ammonia, or in an acidic medium, such as a normal solution of hydrochloric acid! or a solution of formic acid, at a temperature varying from 0" to 707C, depending on the nature of the protective group.

The sequence of these reactions can make it possible to transform derivative formulas! (IM) in the derived formula (1).

Compounds of formula (II) can be obtained: - or by direct alkylation of indolzylamine derivatives of formula (M):

VZ

What's wrong with me?

Kk

Н Formula (U) in which Ki, Az and Va are defined! more, and which are commercially available, or the synthesis of which is described in the following literature:

R.S.OSHSIAM, E.M/.MEMENA apa N.S.RAIMTU, Neiegosusiis Sotroypav, dopp Umieu apa boiv, Ips. Mem Moik 1952, mo!. Hey, dude! 1, pp. 51-57, i

U.NAAGEH-MA5BOM apa A.NOASKBOM, U.Spet. boss. 1954, 1165, with derivative formulas (MI):

B2-(SNeg)n-U is a formula (MI) in which Kg and n are defined! more, U is a halogen atom, preferably chlorine or bromine, in the presence of a metal-containing agent, such as sodium or cast hydride, or sodium or potassium alcoholate, in an organic solvent, such as alcohol or dimethylformamide or M-methylpyrrolidone, at a temperature between 0" and 607C, - or by alkylation of 3-formindole of the formula (MII):

Kk i and NO n

The formula (UP) in which Ni is defined above, with the following derivatives of the formulas: (MI), in the presence of a metal-containing agent, such as sodium or molten hydride, or sodium or potassium alcoholate, in an organic solvent, such as alcohol or dimethylformamide, with the production of derivatives formulas! (MIP):

І and NO pre»

Vo

The formula (USH) in which Vi and Kg and n are determined! more

This derivative is then subjected to interaction with the corresponding nitroalkane in the presence of ammonium acetate to obtain nitrovinyl indoles of the formula (IX):

VZ and Mr. ! And what's more

Formula (IX) in which Ni, RN, Az, Ka, and n are defined! more

This derivative is then restored by catalytic hydrogenation in the presence of Raney nickel or in the presence of lithium aluminum hydride to obtain compounds of the formulas! (II).

Other methods of synthesis of indolethylamine derivatives are mostly described in the literature and can be used. For example, one can note the method of synthesis, which includes the interaction of oxalyl chloride with the corresponding indole, according to the following links:

M.E.ZREEETEK apa M/.S.AMTNOMU, U. At.Spet. wasps 1954, 76, 6208, and further amidation of the product and interaction of the amide functional group with lithium aluminum hydride.

Z-formylindole! formulas! (MY), used in these syntheses, are commercially available or lime! to specialists in this field, for example, from the following links:

Ogdapis bZupipezez SoiY. My. IM, 539, or they can be obtained by methods described in the literature, for example in:

Ogdapis Zupipezez SoiYi., my. IM, 542 b-halogenpurinyi! formula (III) was obtained from inozine by the methods described in the following literature:

A.A.ZSNMIOT apa N.O.EVIT2, Spet. Veg., 1970, 103, 1867,

N.M.KIZBMAM apa mm.mM/E!55 9. Ogud. Spent. 1956, 21, 1053,

V.A. VAKEV, K.NEM/5OM, N.O. TNOMAZ apa U.ADONMBOM OA 9.Oga. Spent 1957, 22, 954,

U. 2 KHEMIISKA apa g. 5OVM, SoiI. Shtesp. Spent Sottype 1965, 30, (6), 1880.

Compounds of formulas (I), as described above, and their addition salts, in particular pharmaceutically acceptable salts, have good affinity for adenosine receptors. This affinity leads to good analgesic activity, as well as hypertensive properties.

Derivative formulas are used with these properties! (I) in therapy, and the invention further applies to products with more than one formula! (I), as drugs, to their salts of addition and, in particular, to pharmaceutically acceptable salts.

Thus, the invention also covers a pharmaceutical composition containing a pharmaceutically effective amount of at least one compound of formula (I) presented above, or one of its pharmaceutically acceptable addition salts, which may or may not be combined with a pharmaceutically acceptable additive, solvent or carrier.

These compositions can be administered by oral, rectal, parenteral, subcutaneous or ocular route of administration.

These compounds can be solid or liquid and can be in pharmaceutical forms commonly used in human medicine, such as, for example, plain or coated tablets, gelatin capsules, suppositories, and preparations for injections. They are obtained in ordinary ways. The active base, which contains a pharmaceutical effective amount of at least one compound of the formulas! (It), specified above, or one of its pharmaceutically acceptable salts, can be mixed with additives commonly used in these pharmacological compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives), cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous solvents, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants! or emulsifiers, silicone gels, some polymer! or copolymer, preservative, flavoring or dyes.

The invention also covers a pharmaceutical composition with analgesic activity, especially successfully used for pain, which contains a pharmaceutically effective amount of at least one compound of the formula! (I), presented above, or one of its pharmaceutically acceptable salts, which may or may not be combined with a pharmaceutically acceptable additive, solvent or carrier.

The invention also covers a pharmaceutical composition with antihypertensive activity, successfully used in hypertension, which contains a pharmaceutically effective amount of at least one compound of the formulas! (I), presented above, or one of the pharmaceutically acceptable salts, which may or may not be combined with a pharmaceutically acceptable additive, solvent or carrier.

The invention covers a method for obtaining a pharmaceutical composition, which includes mixing a pharmaceutically effective amount of at least one compound of the formulas! (1), presented above, or one of the pharmaceutically acceptable salts to a pharmaceutically acceptable additive, solvent or carrier. In one implementation, the obtained pharmaceutical composition with analgesic activity is especially successfully used for pain; in the second case, the obtained pharmaceutical composition with antihypertensive activity is especially successfully used in hypertension.

In the second embodiment, the pharmaceutical composition is prepared in the form of gelatin capsules or tablets containing from 5 to 300 mg of the active ingredient, or as preparations for injections containing from 0.1 to 100 mg of the active ingredient. The composition can also be used! in the form of suppositories, rubs, creams, gels or aerosol preparations.

The invention also covers a method of therapeutic treatment of mammals, which includes the administration of a therapeutically effective amount of at least one combination of formulas to that mammal! (I), as indicated above, or one of its pharmaceutically acceptable salts. In one version of that method of treatment, the combination of formulas! (I) either alone or in combination with a pharmaceutically acceptable additive is used in the form of gelatin capsules or tablets containing from 5 mg to 300 mg of the active ingredient for oral use or in the form of preparations for injections containing from 0.1 to 100 mg of the active ingredient, or, in addition, in the form of suppositories, rubs, creams, gels or aerosol preparations.

When treating a person or an animal, the compound of formula (I) or its salts can be administered by themselves or in combination with a physiologically acceptable additive in any form, in particular in the form of gelatin capsules or tablets for oral administration or in the form of an injection solution for parenteral administration, beat the reviews and other forms! for use in treatment, such as suppositories, rubs, creams, gels or azrosol preparation!.

As will become clear from the pharmacological studies presented at the end of the description, compounds according to the invention can be used in the treatment of humans for the above indications, orally in the form of tablets or gelatin capsules containing from 5 mg to 300 mg of the active ingredient, or parenterally in the form of preparations for injections containing 0.1 to 100 mg of the active ingredient, with one or more doses per day for an adult with an average weight of 60 to 7 kg.

When treating animals, the daily dose that can be used is usually between 0.1 and 5 Ωg per kg when administered by the oral route and between 0.01 and 1 mg per kg when administered intravenously.

Further characteristics and advantages of the invention will be more clearly understood from the subsequent description of some examples, which do not imply a limitation of the invention, but thank you! only for the purpose of his illustration.

Example (1: B-O-Ribofuranuronamido-1-(b-chloro-9H-purin-9-yl)-M-cyclo-propyl-1-deoxy-2,3-O(1-methyl-ztylidene)

She

Formula (PI): X - SI, Ki": s-m - "

Kiz, Ka: isopropylidene 20g, 2 3-O-Isopropylidene-b-chloropurine-5'i-uronic acid, obtained according to ZSNMIOT MK.K. apa

N.O.EVIT2, Spet. Veg 1970, 103(6), 1867 - 71, in 50 g of anhydrous SNCI3, stabilized by amylene, boil under reflux for 5 hours in the presence of 8 bml of 5OSI" and 10 ml of anhydrous DMF.

Excess 5OSI" and solvents are distilled off. The residue is treated with 200 ml of anhydrous chloroform and added dropwise under nitrogen to a mixture of 150 ml of CHCl and 41 ml of cyclopropylamine, previously cooled to 5°C. During the addition of acid chloride, the temperature of the reaction mixture is maintained below 1070.

The mixture is left to react for the next 30 minutes and then washed with a diluted NOSI solution and then with a sodium bicarbonate solution. Finally, they are washed with water, then dried and the solvent is evaporated, resulting in 26.3 g of brown oil.

Purification by chromatography on silica gel (solvent: СНо2Си» 9095 / acetone 1095) will give 15.7 g of p-0-ribofuranoramido-1-(b-chloro-9H-purin-9-yl)-M-cyclopropyl-1-deoxy-2, 3-0-(1-methylethylidene) in the form of an amorphous solid product.

The compounds of examples 2-4 were prepared according to the method of example 1 using the corresponding amines:

Example 2: B-Y-Ribofuranuronamido-1-(6b-chloro-9H-purin-9-yl)-1-deoxy-M-zyl-2,3-0-(1-methylethylidene) 6)

The formula (SHU X- SI, Vikh S rmula (Ш) would s-m -snu-sSn»z,

Kees, Kia: Isopropylidene.

A yellowish oil purified by chromatography on silica gel (eluent: chloroform 9595 / methanol 595) gives a solid product melting at 9170.

Example 3: B-O-Ribofuranuronamido-1-(b-chloro-9H-purin-9-yl)-1-deoxy-M-(1-hydroxy-2-methylpropan-2-yl)-2,3-0 -(1-methylthylidene)

Go) SN

Formula (Ш): X - SI, Co: Yrmula (SI); s- - - mn -:s- sn -on

SN

Kees, Kiel: isopronylidene.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9095 / methanol 10965)

Example 4; VD-O-Ribofuranuronamido-1-(b-chloro-9H-purin-9-yl)1-deoxy-M-isopropyl-2,3-O-(1- methylztylidene) o CHnui

Formula (PP): X - SI, Ku»: Y s - Mkh n --s.,

SNz

Wiz, Vi«: isopropylidene.

Orange oil purified by chromatography on silica gel (solvent: SNCIz 9095 / acetone 1090).

Example 5: 1-(4-chlorobenzyl)-3-formylindole

Formula (MIP): Vi - H, n - 1, B» - 4-chlorophenyl

A solution of 58 g of 3-formindole, 55.9 g of K»CO3 and 70.9 g of p-chlorobenzyl chloride in 200 ml of DMF is refluxed for 2 hours. After cooling, the mixture is poured into 2 liters of water and ground. The resulting precipitate is filtered, washed with water and then treated with isopropanol, filtered,

squeeze out and wash with pentane to obtain 120 g of a cream-colored solid product.

Purification by recrystallization from ethanol gives 84.4 g of 1-(4-chlorobenzyl)-3-formylindole, melting at 122276.

The following compounds of examples 6 - 16 were obtained! according to the method of example 5:

Example 6: 1-Benzyl-3-formylindole

Formula (MIP): Vi - H, n - 1, Vo - phenyl

Recrystallization from ethanol.

Melting point: 11127С (literature: 113 - 114"С-А. КАГИА apa 5.52АВА, U. Mei. Spet. (1966), my. 9, 793).

Example 7: 1-(2,6-Dichlorobenzyl)-3-formylindole

Formula (MIP): Ki 2 H, n - 1, B" - 2,6-dichlorophenyl

Recrystallization from 2-methoxyethanol.

Melting point: 16070.

Example 8: 1-(Naphth-1-ylmethyl)-3-formylindole

Formula (MIP): Vi - H, n - 1, Vo - naphthyl

The resulting solid product is used as such in the next stage.

Example 9: 3-formyl-1-(pyrid-3-yl)indole

Formula (MIP): B - H, n - 1, B" - pyrid-3-yl

Purification by chromatography on silica gel (solvent: SNCIz 9595 / methanol 590).

Melting point: 8895.

Example 10: 1--4-Methylbenzyl)-3-formylindole

Formula (MIP): B - H, n - 1, B" - 4-methylphenyl

The resulting solid product is used as such in the next stage.

Melting point: 11870.

Example 11: 1-(3,4-Dimethylbenzyl)-3-formylindole

Formula (MIP): Vi - H, n - 1, BH» - 3,4-methylphenyl

Brown oil is used as such in the next stage.

Example 12: 1-(2,5-Dimethylbenzyl)-3-formylindole

Formula (MIP): Vi - H, n - 1, A» - 2,5-dimethylphenyl

The resulting solid product is used as such in the next stage.

Melting point: 13970.

Example 13: 1-(2-Methoxystil)-3-formylindole

Formula (MIP): Vi - H, n - 1, B" x methoxy

Brown oil is used as such in the next stage.

Example 14: 1-Cyclopentyl-3-formylindole

Formula (MIP): Vi - H, n - 0, Vo - cyclopentyl

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9095 / methanol 1095).

Example 15: C3-Formyl-1-isopropylindole

Formula (MIP): Vi - H, n - 0, B» x isopropyl

Brown oil is used as such in the next stage.

Example 16: 3-Formyl-1-(2-M-morpholinosyl)indole

Formula (MIP): Vi - H, n - 2, Vo - M-morpholino

The solid product is used as such in the next stage.

Melting point: 80"С.

Example 17: 1-(4-Chlorobenzyl)-3-(2-nitrovinyl)indole

Formula (IX): Ni 2 H, n - 1, Bo - 4-chlorophenyl, Ez - Na - H 80.9 g of 1-(4-Chlorobenzyl)-3-formylindole, obtained in example 5, 18 g of ammonium acetate and ZbO0 ml of nitromethane boil under reflux for 30 minutes.

After cooling, an orange precipitate appears. It was filtered and washed with water and then with isopropanol and hexane to obtain 81.1 g of orange crystals of 1-(4-chlorobenzyl)-3Z(2-nitrovinyl)indole.

Melting point: 17870.

Nitrovinylindol! examples 18 - 28 were obtained according to the method of example 17:

Example 18: 1-Benzyl-3-(2-nitrovinyl)indole

Formula (IX): Bi 2 H, n - 1, B» - phenyl, Ez - Ba - H

Melting point: 13070.

Example 19: 1-(2,6-Dichlorobenzyl)-3-(2-nitrovinyl)indole

Formula (IX): Ni 2 H, n - 1, B" - 2,6-dichlorophenyl, Kz - Na - H

Melting point: 1707

Example 20: 1-Naphthylmethyl-3-(2-nitrovinyl)indole

Formula (IX): Ni 2: H, n - 1, Vo - naphthyl, Kz - H4 2 H

Melting point: 19670

Example 21: 1-"Pyrid-33-ylmethyl)-3-(2-nitrovinyl)indole

Formula (IX): Ni 2 H, n - 1, Vo - pyrid-Z3-yl, Kz - Na: H

Melting point: 165 - 17070

Example 22: 1-(4-Methylbenzyl)-3-(2-nitrovinyl)indole

Formula (IX): Ni 2 H, n - 1, Vo - 4-methylphenyl, Kz - Na: H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 23: 1-(3,4-Dimethylbenzyl)-3-(2-nitrovinyl)indole

Formula (IX): Ni - H, n - 1, Rg - 3,4-dimethylphenyl, Kz - Na x H

Melting point: 13570.

Example 24: 1-(2,5-Dimethylbenzyl)-3-nitrovinylindole

Formula (IX): Vi - H, n - 1, B» - 2,5-dimethylphenyl, Kz - Ba - H

Melting point: 1457c

Example 25: 1-(2-Methoxyethyl)-3-(2-nitrovinyl)indole

Formula (IX): Vi - H, n - 2, B» - methoxy, Kz - Ba - H Melting point: 13270

Example 26: 1-Cyclopentyl-3-(2-nitrovinyl)indole

Formula (IX): Ni - H, n - 0, No - cyclopentyl, Nz - Na: N

Orange oil purified by chromatography on silica gel. Solvent: methylene chloride.

Example 27: 1-Isopropyl-3-(2-nitrovinyl)indole

Formula (IX): Ni - H, n - 0, Vo x isopropyl, Kz - Na: H

Orange oil is used as such in the next stage.

Example 28: 1--2-K-Morpholinostil)-3-(2-nitrovinyl)indole

Formula (IX): Ni 2 H, n - 2, Vo - M-morpholino, Ez - Na: H

Melting point: 11476.

Example 29: 1-(4-Chlorobenzyl)-3-(2-aminosyl)indole Formula (1): Vi - H, p - 1, A» - 4-chlorophenyl, Kz - Ba - H Add 52.5 g of Hy AINA in small portions to 500 ml of anhydrous TTF. The temperature is allowed to rise to 50"C. Without cooling this solution, a solution of 78.2 g of 1-(4-chlorobenzyl)-3-(2-nitrovinyl)indole, obtained according to example 17, is introduced dropwise into 1000 ml of anhydrous TTF.

The mixture is boiled in a reflux refrigerator for 1 hour and 30 minutes and cooled.

A saturated aqueous solution of Ma»5Og is introduced dropwise, and the mixture is filtered through celite 545. After decantation, the organic base is concentrated to obtain an orange oil.

The compound is first purified by distillation (boiling point: 180 - 188"C at 0.1 mm Hg) and then recrystallized from ethanol to obtain 38.1 g of 1-(4-chlorobenzyl)-3-(2-aminoacetyl)indole hydrochloride.

Melting point of the base: 8770.

Melting point of hydrochloride: 21270.

Example 30: 1-(4-Chlorobenzyl)-3-(2-aminoacetyl)indole

Formula (1): Vi - H, n - 1, B» - 4-chlorophenyl, Kz - Na: H 10 g of Z-aminostilindole dissolve in 50 cm? DMF. Then add 5.6 g of Man (6095).

The mixture is stirred at room temperature for 30 minutes.

A solution of 11.2 g of p-chlorobenzyl chloride in 10 ml of DMF is added dropwise. The mixture is heated at 55"7C for 2 hours and cooled. The insoluble material is filtered off. The filtrate is concentrated in vacuo, and the residue is treated with methylene chloride and washed with water. After drying, the organic phase is concentrated to obtain 20.4 g of brown oil.

Purification by chromatography on silica gel (solvent: CHSiz 9595 / isopropylamine 595) gives 9.7 g of 1-(4-chlorobenzyl)-3-(2-aminoethyl)indole.

Hydrochloride melting point: 21470.

The following compounds of examples 31 - 45 were obtained by one of the methods of examples 29 - 30:

Example 31: 1-Benzyl-3-(2-aminoacetyl)indole

Formula (II): Vi - H, n - 1, B» - phenyl, Kz - Na: H

The hydrochloride is purified by recrystallization from isopropanol.

Melting point: 176 - 17870.

Example 32: 1-(2,6-Dichlorobenzyl)-3-(2-aminoacetyl)indole

Formula (II): Vi - H, n - 1, B» - 2,6-dichlorophenyl, Kz - Vy: H

Melting point: 6870.

Example 33: 1-Naphthylmethyl-3-(2-aminoacetyl)indole

Formula (II): Vi - H, n - 1, B" x naphthyl, Kz - Na: N

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 34: 1-"Pyrid-3-ylmethyl)-3-(2-aminoacetyl)indole

Formula (1): B - H, n - 1, B" - pyrid-3-yl, H3 - Na: H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 35: 1-(4-Methylbenzyl)-3-(2-aminoacetyl)indole

Formula (I): A 2 H, n - 1, B" - 4-methylphenyl, Kz - Na x H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 36: 1-(3,4-Dimethylbenzyl)-3-(2-aminoacetyl)indole

Formula (I): Ni 2 H, n - 1, B" - 3,4-methylphenyl, H3 - Na: H

Colorless oil purified by chromatography on silica gel (solvent: methylene chloride 9595 / isopropylamine 595).

Example 37: 1-(2,5-Dimethylbenzyl)-3-(2-aminoacetyl)indole

Formula (II): Vi - H, n - 1, P» - 2,5-dimethylphenyl, Kz - Na - H

Orange oil purified by chromatography on silica gel (solvent: methylene chloride 95960/isopropylamine

Bob).

Example 38: 1-(2-Methoxyethyl)-3-(2-aminoethyl)indole

Formula (II): Vi - H, n - 2, Vo x methoxy, Kz - Na: H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9095 / isopropylamine 109).

Example 39: 1-Cyclopentyl-3-(2-aminoacetyl)indole

Formula (I): Vi 2 H, n - 0, B" x cyclopentyl, Kz - Na x H

Yellowish oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 40: 1-Isopropyl-3-(2-aminoacetyl)indole

Formula (II): Vi - H, n - 0, B» x isopropyl, Kz - Ba: H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 41: 1-(2-M,M-Dimethylaminoacetyl)-3-(2-aminoacetyl)indole

Formula (I): Bi 2 H, n - 2, B» - M,M-dimethylamino, Kz - Ba - H

Orange oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 42: 1--2-M-Morpholinostil)-3-(2-aminostil)indole

Formula (I): B 2 H, n - 2, B» - M-morpholino, Kz - Ba - H

Orange oil, purified by chromatography on silica gel (solvent: reform 9595 / isopropylamine 5905),

Example 43: 1--2-M-Piperidinosyl)-3-(2-aminosyl)indole

Formula (I): B 2 H, n - 2, B" - M-piperidino, Kz - Ba - H

Orange oil purified by chromatography on silica gel (solvent: methylene chloride 9595 / isopropylamine

Bob).

Example 44: 1-(M-Pyrrolidinosyl)-3-(2-aminosyl)indole

Formula (I): Vi - H, n - 2, B» - M-pyrrolidino, Kz - Ba - H

Orange oil purified by chromatography on silica gel (solvent: methylene chloride 9595 / isopropylamine

Bob).

Example 45: 1-(3,4-Dichlorobenzene)-3-(2-aminoacetyl)indole

Formula (II): B - H, n - 1, B" - 3,4-dichlorophenyl, H3 - V : H

Melting point: 19670.

Example 46: D-O-Ribofuranuronamido-1-/6-//2-/1-(4-chlorobenzyl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/-K-cyclopropyl- 1-deoxy-2,3-0-(1-methylthylidene)

Formula (IM): Ku - H, n - 1, K. - 4-chlorophenyl, Kz - K. - H,

She

Ve: -d »pt'os-A-kn,

SN. about / Z

WITH

Kees, Ki - ra

SN

In a nitrogen atmosphere, suspend 49 g of 1-(4-chlorobenzyl)-3-(2-aminoethyl)indole hydrochloride, obtained by one of the methods of examples 29 or 30, in 100 ml of ethanol. The suspension is neutralized with 5.1 ml of trisethylamine, then 4.1 g of p-Y -ribofuranoramido-1-(b-chloro-9H-purin-9-yl)-M-cyclopropyl-1-deoxy-2,3-0-(1-methylthylidene) obtained according to example 1.

Everything is boiled with a reflux refrigerator for 7 hours and left to stand all night. The solvent is evaporated, and the residue is treated with chloroform, washed with water, dried and concentrated.

The resulting solid residue is chromatographed on silica gel (solvent: chloroform 9095 / methanol 1095) to obtain 7.2 g of an amorphous solid product.

The production of examples 47 - 59 was obtained in the form of amorphous solid products according to the method of example 1:

Example 47: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-methoxyzyl)indol-3-yl/zyl/amino/-9H-purin-9 -yl/-2,3-0-(1-methylostylidene).

Formula (IM): Ku, - H, n -2, Co - methoxy, Kz - VE, - H,

She

You A toast Mn ' sn zhi h

Keys, Key - 133,414 in St

Example "48: B-O-Ribofuranuronamido-1-/6-//2-/1-cyclopentylindol-3-yl/ztyl/amino/-9H-purin-9-yl/-M-cyclopropyl-1-deoxy- 2,3-0-(1-methyl-thylidene).

Formula (IM): K, - H, n - 0, Ko x cyclopentyl, Kz x K. - H, o

Ki: D| /h

Сs-- k5n ' sn o Z

Ki" Kia r

SNz

Example 49: VD-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-isopropylindol-3-yl/-ztyl/-amino/-9H-purin-9-yl/ -2,3-0-(1-methylostylidene).

Formula (IM): K, - H, n 0, K» - isopropyl, Kz - K. - H, o

Ko b kn , same SN

Viz, V. 54 133 4 4 SN

Example 50: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(4-methylbenzyl)indol-3-yl/ztyl/amino/-9H-purine-9 -yl/-2,3-0-(1-methylostylidene).

Formula (IM): Ki - H, n "1, K" - 4-methylphenyl, Kz - K. - H,

She

Co. 5 th pony, m. SN

KIV 4 13, Their 4 SN

Example 51: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(3,4-dimethylbenzyl)indol-3-yl/ztyl/amino/-9H-purine -9-yl/-2,3-0-(1-methyl-ztylidene).

Formula (IM): K, - H, n with 1, K; - 3,4-dimethylphenyl, Kz - K. - H, o

Let her be judged, sleep with

Kiz Ka - ra Ya

SNz

Example 52: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-indol-3-yl/-ztyl/amino/-9H -purin-9-yl/-2,3-0-(1-methylthylidene).

Formula (IM): K, - H, n - 1, K»-2,5-methylphenyl, Kz - K.- H,

She

Who is her days of THEM; sleep about Z

Kz, Kia - ra M,

SN

Example 53: D-SO-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M-morpholinostil)indol-3-yl/ztil/amino/-9H-purine -9-yl/-2,3-0-(1-methylostylidene).

Formula (TU): Ki - H, yak t 2, K» morpholino, Kz - K.- H,

Ko - Y sn-- , ke SN I su

I» Kia ' 4 SN

Example 54: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M,M-dimethylaminoethyl)indol-3-yl/ztyl/amino/-9H -purin-9-yl/-2,3-0-(1-methylostylidene).

Formula (TU): K, - H, n -2, K» - M,.M-dimethylamino, Kz - K. - H,

She

Ki» sh- Her dreams 4, vch sn

Enter 13 14 - " 4 CH

Example 55: VD-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-2,3-0-(1-methylztylidene) 1-/6-//2-/1-(2-IM-piperidinostil)indole-3Z -yl/ztyl/amino/-9H-purin-9-yl/.

Formula (IM): K. - H, yah -2, Co - M-piperidino, Kz - K. - H,

Ko - Y. sunA AH, we are from

Keys, Ka - M

Kk SN

Example 56: D-SO-Ribofuranuronamido-M-cyclopropyl-1-deoxy-2,3-0-(1-methylethylidene)-1-/6-//2-/1-(2-M-pyrrolidinosyl)indole- C-yl/zyl/amino/-9H-purin-9-yl/.

Formula (IM): K, - H, yah - 2, K» - M-pyrrolidino, Kz - K.- H,

Ku - yi pon ih ' sn

We ho

Ki. Ka - 135 44 in sleep

Example 57: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy)-1-/6-//2-/1-(3,4-dichlorobenzyl)indol-3-yl/ztyl/amino/-9H- purin-9-yl/-2,3-0-(1-methylostylidene).

Formula (IM): B. - H, n - 1, K» - 3,4-dichlorophenyl, Kz - K. - H,

She

Ko-M kn,

SN.

WE

M

Ki. Ky - 133 ГчЧ4 ra NE

Example 58: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-2,3-0-(1-methylethylidene)-1-/6-//2-/1-(pyrid-3-ylmethyl)indol- C-yl/zyl/amino/-9H-purin-9-yl/.

Formula (IM): K, - H, yah - 1, Ko» - pyrid-3-nl, Kz - K. - H,

How many days are there,

SN. we are

KE, Ka 133 714 / SN

Example 59: D-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-2,3-0-(1-methylztylidene)-1-/6-//2-/1-(naphth-1-ylmethyl)indol- C-yl/zyl/amino/-9H-purin-9-yl/.

Formula (IM): K, - H, n - 1, K; - naphth-1-yl, Kz - K, - H,

HER

Ko - Her Mon, about CH 4

Kis, Ky - 13» 114 ra SN

The compounds of example 60 were prepared according to the method of example 46, using the uronamide obtained according to example 3:

Example 60: D8-O-Ribofuranuronamido-1-/6-//2-/1-(4-chlorobenzyl)indol-3-yl/ztyl/amino/-9UN-purin-9-yl/-1-deoxy- M-(1,1-dimethyl-2-hydroxyethyl)-2,3-0(1-methylethylidene)

Formula (IM): Vi - H, n - 1, A» - 4-chlorophenyl, Kz - Na - H, sn,

B - 12 7 sSK-- Mn and -'s--sn.,on o sn, sn - Z

V. v,.- ry yo sn,

Example 61: p-O-Ribofuranuronamido-1-/6-//2-/1-(4-chlorobenzyl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/-M-cyclopropyl- 1-deoxy.

Formula (I): K, - H, n - 1, K» - chlorophenyl, Ez - K, - H, - su. 7.2 g of purine obtained in example 46 is placed in 135 ml of 1 M NOSI. The mixture is heated at 60°C for 1 h and cooled. The solution is decanted to separate the aqueous phase from the more or less viscous resin formed. The aqueous phase is neutralized with sodium bicarbonate solution and extracted with chloroform. The organic phases are combined with the previously obtained resin. The mixture is diluted with water, dried and concentrate to obtain 7 g of a cream-colored solid residue.

The compound is purified by chromatography on silica gel (solvent: chloroform 9595 / methanol 595) to obtain 3.7 g of 8-Y-Ribofuranuronamido-1-[6-//2-1-(4-chlorobenzyl)indol-3-yl/zyl/amino /-9H-purin-9-yl/-A-cyclopropyl-1-deoxy.

The empirical formula is: SzoNzoSIM7Om4.

Melting point: 22576.

The same compound 61 can be obtained by hydrolysis in a medium of formic acid! (212 ml of 5095 solution) when heated at 70"7C for 75 minutes.

Combinations of examples 62 - 75 were obtained! according to example 61: Example 62: D-Y-Ribofuranuronamido-1-16-/2-/1-(4-chlorobenzyl)indol-3-yl/ztyl/amino/-UN-purin-9-yl/-1- deoxy-M-(1,1-dimethyl-2-hydroxyethyl).

Formula (I): K, - H, n ": 1, Ko" - 4-chlorophenyl, Kz - K. -e H,

AND"

Ki- nt - -sNoonN,

SN

Purification by chromatography twice! sequentially on silica gel solvent: chloroform 9095 / methanol 1090).

The empirical formula is: SziNzaSIM7O5.

Melting point: 18970.

Example 63: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-methoxyzyl)indol-3-yl/zyl/amino/-9H-purin-9 - ill.

Formula (1): K, - H, n -2, Co - methoxy, Kz - K- H,

Wash - me / M,

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula is: SgviNziM7O5.

Melting point: 13270.

Example 64: D-O-Ribofuranuronamido-1-/6-//2-/1-cyclopentyl-indol-3-yl/ztyl/amino/-9H-purin-9-yl/-M-cyclopropyl-1-deoxy .

Formula (1): KE - H, n "0, Ko" - cyclopentyl, Kz xx Ka - H,

Ko -ky-« | '

Purification by silica gel chromatography (solvent: chloroform 9595 / methanol 5965).

The empirical formula: СгвНззинН?Ох.

Melting point: 14176.

Example 65: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-[6-//2-/1-isopropylindol-3-yl/-ztyl/amino/-9H-purin-9-yl/.

Formula (1): K, - H, n - 0, Co - cyclopentyl, Kz - K.- H,

E5- -ky-s:

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula is: SgviNziM7O5.

Melting point: 13570.

Example 66: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-(1-methylbenzyl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/ .

Formula (1): Ku - H, n - 1, K» - 4-methylphenyl, Kz - K. - H,

KE; -kn-U«5 '

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula: CziNzzM7Ol, NgO.

Melting point: 14476.

Example 67: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(3,4-dimethylbenzyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (I): Ki - H, n 1, K» - 3,4-dimethylphenyl, Kz - K. - H,

B5- -kn-f33 '

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula: Cz2Hz5M7Ol, HgO.

Melting point: 13476.

Example 68: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (1): K. - H, n - 1, KE" - 2,5-dimethylphenyl, Ez - K. - H,

E5- -ky-sh« | ;

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula: Cz2Hz5IM7Oa, 0.5 NgO.

Melting point: 13070.

Example 69: D-SO-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M-morpholinostil)indol-3-yl/ztil/amino/-9H-purine -9-il/.

Formula (1): K, - H, n -.2, Ko» - M-morpholino, Kz - B. - H,

VK: -ky-( '

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula is: SgoNzeMveO5, 0.5 NgO.

Melting point: 109 - 11070.

Example 70: B-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M,M-dimethylaminosyl)indol-3-yl/ztyl/amino/-9H -purin-9-yl/.

Formula (I): K, - H, n - 2, Ko - M.M-dimethylamino, Kz - K. - H,

Vz- -KkNA-« 1.

Purification by chromatography on silica gel (solvent: chloroform 8095 / isopropylamine 2095).

Chemical formula: C27HzaMovOa, 0.5 NgO.

Melting point: 11270.

Example 71: 8-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M-piperidinosyl)indol-3-yl/zyl-amino/-9H-purine -9-ili/.

Formula (1): K, - H, n -2, KE" - M-piperidico, Kz - K. -1I

Wu 7 H--O

Purification by chromatography on silica gel (solvent: chloroform 8095 / methanol 20965).

Zmpirical formula: SzoNzaMvOm.

Melting point: 10970.

A solution of 11 g of the compound obtained in this way in 100 ml of ethanol is introduced dropwise into a solution of 3.7 g of citric acid in 40 ml of ethanol. The mixture is stirred for 17 hours at room temperature.

The resulting solid product is filtered off, washed with ethanol and dried to obtain 10.6 g of citrate B-O-ribofuranoramido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M-piperidinosyl)indole- 3-yl/ztyl/amino/-9H-purin-9-yl/.

The empirical formula: SzoNzaMvOl4, SeNgO".

Melting point: 13870.

Example 72: 8-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M-pyrrolidinosyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (1): K, - H, n - 2, K; - M-pyrrolidino, Kz x K. - H,

B5- -kn-e35 '

Purification by chromatography on silica gel (solvent: chloroform 8095 / methanol 20965).

The empirical formula is: SgoNzeMaOal 0.5 NgO.

Melting point: 12670.

Example 73: VD-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(3,4-dichlorobenzyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (I): Ki - H, n 1, K» - 3,4-dichlorophenyl, Kz - K. - H,

KE, sh -ky-f« ,

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula is: SzoNgOSi2M7O", 0.8 NgO.

Melting point: 14176.

Example 74: D8-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(pyrid-3-ylmethyl)indol-3-yl/-ztyl/amino/-9H- purine-9-yl/.

Formula (1): K, - H, n - 1, Ko" "x pyrid-3-yl, Kz - K. - H,

Purification by recrystallization from 2-methoxyethanol.

The empirical formula is: СгеНзоМвОч4, 0.5СНзО СНгСНОН.

Melting point: 23970.

Example 75: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(naphth-1-ylmethyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (1): Ku - H, n - 1, K» - naphth-1-yl, Kz: K, - H,

E, t- -kk-« z

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5950) with recrystallization from isopropanol.

Zmpirical formula: SzaNzziM7Ox.

Melting point: 16870.

Example 76: Mb-/2-/1-(4-chlorobenzyl)indol-3-yl/zyl/adenosine.

Formula (IM): Ki - H, n 5 1, Y - 4-chlorophenyl, Kz - K4 - H,

Ki - CHNOOH, Kis - Kia - N. 4.5 g of 1-(4-chlorobenzyl)-3-(2-aminosyl)indole hydrochloride, obtained according to example 29 or 30, is placed in 100 ml of ethanol. Add 2.1 g of triztylamine and then 2 g of b-chloroadenosine.

Everything is boiled with a reverse refrigerator for two hours. They are cooling. The obtained residue is filtered and washed with ethanol and then with ether.

Recrystallization from ethanol gives 2.5 g of Mb-/2-/1-(4-chlorobenzyl)indol-3-yl/ztyl/adenosine.

Melting point: 18170.

The compounds of examples 77 and 78 were obtained according to example 76:

Example 77: Me-/2-/1-benzylindole-3-yl/zyl/adenosine.

Formula (IM): K, - H, n - 1, K» - phenyl, Kz - K.- H,

Ki - SN.ON, Kz B Kia - N.

Purification by recrystallization from ethanol.

Melting point 15870.

Example 78: Me-/2-/1-(2,6-dichlorobenzyl)indol-3-yl/zyl/adenosine.

Formula (IM): K, - H, n - 1, Co - 2,6-dichlorophenyl, Ez - K. - H,

Ko - SON, Keys sh- Kia - N.

Purification by recrystallization from ethanol.

Melting point 19270.

Alcohols of examples 76, 77, 78 can be oxidized to acids by interaction with an oxidizing agent, such as chromium trioxide, in acetone in the presence of sulfuric acid! or potassium permanganate in water in the presence of ammonia. They will successively form the corresponding acid chloride! after interaction with thionyl chloride and then the production of ribofuranuronamide of the same type as in examples 61, 62, 73 or 75 by interaction with the corresponding amines.

The compounds of examples 79 - 100 were obtained according to example 61.

Example 79: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(pyrid-2-ylmethyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (1): K, - H, n - 1, K", - pyrid-2-yl, Kz - K.- H,

IS; sh- -ky-« 3 z

Purification on three consecutive columns (solvent: chloroform 9095 / methanol 1095, chloroform 8095 / isopropylamine 2095 and methylene chloride 9095 / methanol 1095, respectively).

Zmpirical formula: SgoNzoMvOm.

Melting point: 12276.

Example 80: B-Y-Ribofuranuronamido-1-/6-//2-/1-(4-chlorobenzyl;)-5-chloroindol-3-yl/ztyl/-amino/-9H-purin-9-yl/ -M-cyclopropyl-1-deoxy.

Formula (1): Ku - 5-СЙ, item 51, Ko - 4-chlorophenyl, Kz - Ka. - N,

E.- --MN-- « |.

Purification by crystallization on an isopropanol / sulfur mixture. The empirical formula: SzoNgoSi2M7Ol.

Melting point: 15476.

Example 81: 8-O-Ribofuranuronamido-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-chloroindol-3-yl/ztyl/-amino/-9H-purin-9-yl /-M-cyclopropyl-1-deoxy.

Formula (1): Ku - 5-SI, n - 1, Ko - 2,5-dimethylphenyl, Kz - K. - H,

Ki -kn-f4«5 ,

Recrystallization from ethanol with animal charcoal treatment.

The empirical formula: Cz2HzaSIM?O4; 1.1 NgO.

Melting point: 13970.

Example 82. M-(2-methoxystil).

Formula (1): K, - H, n 1, Ko - 4-chlorophenyl, Kz - K. - H,

EE - -MN-SN.ASNO.-OSN.

Cleaned by processing with hot ethanol.

The empirical formula: CzoHz2gSIM7O5.

Melting point: 19370.

Example 83: pD-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-allylindol-3-yl/ztyl/amino/-9H-purin-9-yl/,

Formula (I): K, - H, n - 1, K; --НС-СН», Ez - K. - H, vE5- -ky-f53 ;

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula: СгвНгоМ7О4; 9H2gO.

Melting point: 11770.

Example 84: VD-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(prop-2-ynyl)indol-3-yl/ztyl/amino/-9H-purine -9-il/.

Formula (1): K, - H, n 5 1, KK» --С EE СН, Kz « KK. - N,

Vv- -kn-f« 5

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula: SgviHg7M7O4; NGO

Melting point: 12370.

Example 85: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-methylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/.

Formula (I): K, - 5-CH», n: 1, B» - 2,5-dimethylphenyl, Kz - K. - H,

W -MNA-«f

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

Zmpirical formula: SzzNz?7M7Ol; 0.8 NgO.

Melting point: 12970.

Example 86: D-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-methoxy-indol-3-yl/ztyl/amino /-9H-purin-9-yl/,

Formula (1): K, - 5-OSH», n - 1, Ko» - 2.5-dimethylphenyl, Kz - K. - H,

KE; -ky-f";

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula: СззНз?М7О5; 0.1 NgO.

Melting point: 18270.

Example 87: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-2-methylindol-3Z-yl/ztyl/amino/- 9H-purin-9-yl/,

Formula (I): Ki -2-CH, n 1, EK. - 2,5-dimethylphenyl, Kz - K« - H,

KE - -ky-s 3,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

Zmpirical formula: SzzNz?7M7Ol; 0.7 NgO.

Melting point: 14476.

Example 88: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(4-methoxybenzyl)indol-3-yl/ztyl/amino/-9H-purin-9 -il/.

Formula (1): K. - H, n xx 1, K, - 4-OSH:-phenyl, Ez - K. - H,

E5- -ky-f 3,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10965).

The empirical formula: CziNzziM7O5; 0.8 NgO.

Melting point: 13476.

Example 89: p-O-Ribofuranuronamido-1-/6-//2-/1-cyclopentyl-2-methyl-indol-3-yl/ztyl/amino/-9H-purin-9-yl/-M-cyclopropyl -1-deoxy.

Formula (1): Ku - 2-CH», n -: 0, KE» - cyclopentyl, Kz - K4 - H, shsh -ky-f« y

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10965).

The empirical formula is: СгеНз5М7О4.

Melting point: 14070.

Example 90: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M,IM-dimethylaminobenzyl)indol-3-yl/ztyl/amino/-9H -purin-9-yl/.

Formula (1): Ku - H, n "g 1, K" - 2-M.M-dimethylaminophenyl, Kz - K.4 - H,

EC; -kn-f«,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10965).

The empirical formula: Cz2NzeMaOx.

Melting point: 128 - 129760.

Example 91: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(3-nitrobenzyl)indol-3-yl/ztyl/amino/-9H-purin-9 -il/.

Formula (1): K, - H, n - 1, Ko» - 3-MO»-phenyl, Kz - K. - H,

B5- -ky-( ,

Purification by chromatography twice successively on silica gel (solvent: chloroform 9095 / methanol 1095 and methylene chloride 9095 / methanol 1095, respectively).

Zmpirical formula: SzoNzoMvObv; 0.3 NgO.

Melting point: 12970.

Example 92: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//1-/1-(2,5-dimethylbenzyl)indol-3-yl/propan-2-yl/amino/ -9H-purine-9-yl/.

Formula (1): K, - H, n x 1, K»-2,5-dimethylphenyl, Kz - Ka. - SN",

E- -kk-« ,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula is: СззиНз7М7О4.

Melting point: 13570.

Example 93: D-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//1-/1-cyclopentylindol-3-yl/propan-yl/amino/-9H-purin-9-yl/ .

Formula (1): K, - H, n - 0, K, - cyclopentyl, Ez - H, K. - SV»

EE - -ky-( ,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula is: СгеНз5М7О4.

Melting point: 13070.

Example 94: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)indol-3-yl/propyl/amino/-9H-purine -9-il/.

Formula (I): K, e H, n - 1, K» - 2,5-dimethylphenyl, Kz - CHz, K. - H,

B5- -ky-(5 ;

Purification by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The empirical formula is: СззиНз7М7О4.

Melting point: 13770.

Example 95: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-2-phenylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/.

Formula (1): Ki - 2-phenyl, n - 1, Ko» - 2,5-dimethylphenyl, Kz - K4 - H,

In -kn-.O3,

Purification by chromatography on silica gel (solvent: chloroform 9095 / methanol 10905).

The empirical formula is: SzviNzeM7O4.

Melting point: 13670.

Example 96: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-thiomethylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/,

Formula (1): Ku - 5-5СН», n: 1, Ko - 2,5-dimethylphenyl, Kz - Ku - H,

БЕ5- -кк-с 3 '

The empirical formula: CzzHz7MoO45, 0.8 NgO.

Melting point: 13770.

Example 97: D-O-Ribofuranuronamido-1-/6-//2-/1-(5-chlorothien-2-yl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/- M-cyclopropyl-1-deoxy.

Formula (1): Ku - H, n - 1, Co - 5-chlorothien-2-yl, Ez - K- H,

E5- -kn-K( | ,

Purified by chromatography on silica gel (solvent: chloroform 90595 / methanol 1095).

The empirical formula: SgvNgvSIM7O45, 1 NgO.

Melting point: 13770.

Example 98: D-Y-Ribofuranuronamido-M-cyclopropyl-1-/6-//2-/1-(cyclopropylmethyl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/-1- deoxy

Formula (1): KE, - H, n - 1, Ko" - cyclopropyl, Kz - K. - H,

K5- -kv-a2Iiz,

Chemical formula: C27NziM7O4 5NgO.

Melting point: 13476.

Production according to examples 99 - 118 was obtained in the form of amorphous solid products according to the method of example 46, using the corresponding uronamide of the formula (IP).

Example 99: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(pyrid-2-ylmethyl)indol-3-yl/ztyl/amino/-9H-purine -9-yl/-2,3-0-(1-methylostylidene).

Formula (IM): K, - H, n xx 1, K» - pyrid-2-yl, Kz - KAN, o

Ki» - -- -MmkhN sn r s

You You Ying

Example 100: D-O-Ribofuranuronamido-1-/6-//2-/1-(4-chlorobenzyl)-5-chloroindol-3-yl/ztyl/(amino/-9H-purin-9-yl/- M-cyclopropyl-1-deoxy-2,3-0-(1-methylthylidene).

Formula (IM): Ku - 5-SI, n - 1, K; - 4-chlorophenyl, Kz - K. - H,

She

Ki -E-ki-s m SN

In KE p 135 114 ' and SN

Example 101: D-O-Riofuranoramido-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-chloroindol-3-yl/ztyl/amino/-9H-purin-9-yl/ -M-cyclopropyl-1-deoxy-2,3-0O-(1-methylthylidene).

Formula (1M): Ki - 5-SI, n 1, Ko - 2,5-dimethylphenyl, Kz - KA - H,

Ky- -- -KhN about SN su

You" Kit sn

Example 102. M-(2-methoxyethyl)-2,3-0-(1-methylostylidene).

Formula (IM): K, - H, n "1, Ko" - 4-chlorophenyl, Kz - Ka. - H, 0);

Who: Y - s - - "MNA-sN.-SNU-OsSN"z,

M SN

Vshvn- MA 13 14 - " 4 stv

Example 103: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-allylindol-3-yl/ztyl/amino/-9H-purin-9-yl/-2 ,3-0-(1-methylthylidene).

Formula (IM): Ki - H, n 5 1, YUK, « ztenil, Kz - K. - H, (6)

Ku» - -s-- МН he СН; with

You are Art

Example 104: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-propargylindol-3-yl/ztyl/amino)/- 9H-purin-9-yl/- 2,3-0-(1-methylthylidene).

Formula (IM): K, - H, n - 1, Ko» - ztynyl, Kz - KE. - NN,

She

Ky - --s--nn-- sn to y

Ki" Kit and M

SN

Example 105: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-methylindol-3Z-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylostylidene).

Formula (TU): Ki - 5-CH», p: 1, Ko - 2,5-dimethylphenyl, Vaz - Ka - H,

Co -t DI -s- --«/

CC SN. 54

E. sh- 133 Ka ud SVU

Example 106: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-methoxyindol-3-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylostylidene).

PU formula): K, - 5-OSN", n "1, K" - 2,5-dimethylphenyl, Kz - K. - H,

She

Ki -s-ki-3

SN

We

Kz, V also 133 14 4 SN

Example 107: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-2-methylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylostylidene).

Formula (IM): Ki - 2-CH», p x 1, Ko - 2,5-dimethylphenyl, Kz - Ka - H,

She

Goats - --ky-s

M/S 54

Keys, Ky - 1353 214 in SNU

Example 108: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(4-methoxybenzyl)indol-3-yl/ztyl/amino/-9H-purin-9 -yl/-2,3-0-(1-methylostylidene).

Formula (U): K, - H, n - 1, Ko - 4-OSH-phenyl, Kz - K., - H, o,

Ko - ЯИ - s - -Mkh 6.: SN 54

Ki» Tu St

Example 109: B-O-Ribofuranuronamido-1-/6-//2-/1-cyclopentyl-2-methyl-indol-3-yl/ztyl/amino/-9H-purin-9-yl/-M-cyclopropyl -1-deoxy-2,3-F0(1-methylthylidene).

Formula (IM): K. - 2-CHz, n - 0, KE" - cyclopentyl, Kz - K. - H, o)

Ko - Y -s-- MN

M SN su

Vito St

Example 110: D8-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-M,M-dimethylaminobenzyl)-indol-3-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylthylidene).

Formula (IM): Ku - H, n - 1, K» - 2-M,M-dimethylaminophenyl, Kz-Ka- H,

She

Co -

From - --Mkh 6 same SN 54

Kiz Ka - 133,214 ra stv

Example 111: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(3-nitrobenzyl)indol-3-yl/ztyl/amino/-9H-purin-9 -yl/-2,3-0-(1-methylostylidene).

Formula (IM): K, - H, n - 1, K» - Z-nitrophenyl, Kz - K. - H,

Ko;- Y -s-ky-1 35 54

Kiz Vmkh Sn

Example 112: D-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)indol-3-yl/-propan-2-yl/amino /-9H-purin-9-yl/-2,3-0-(1-methylztylidene).

Formula (IM): K, - H, n - 1, K» - 2,5-dimethylphenyl, Kz - H, KE. - SN", (0)

Ki» - Y - s - Mch o st 54

Ki, Ka -

I3» 14 in SN

Example 113: D-Y-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//1-/1-cyclopentylindol-3-yl/propan-2-yl/amino/-9H-purin-9- il/-2,3-0-(1-methylthylidene).

Formula (IM): K, - H, n 0, Ko» x cyclopentyl, Kz - H, K. - CH»z,

She

Tu --6--Jan-« 7 me SN, 54

Kiz Ka - 135 114 I su

Example 114: dD-YOO-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-indol-3-yl/- propyl/amino/-9H -purin-9-yl/-2,3-0-(1-methylthylidene).

Formula (IM): K, - H, n 5 1, K» - 2,5-dimethylphenyl, Kz - CHz, Kk - H, o

Ko - - s--MkhN about CH 54

Visa Kt Art

Example 115: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-2-phenylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylthylidene).

Formula (IM): Ki - 2-phenyl, n ": 1, Ko" - 2,5-dimethylphenyl, Kz - K. - H,

She

Goats -s-ky-" 3

SN.

WE

Viz V r 133 cha

SN

Example 116: B-O-Ribofuranuronamido-M-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-thiomethylindol-3-yl/ztyl/amino/- 9H-purin-9-yl/-2,3-0-(1-methylostylidene).

Formula (IM): Ku - 5-5СН», n - 1, Ko»-2,5-dimethylphenyl, Kz - K. - H,

She

Ky -s--kn-0

SN. about introduced

Square and

SN

Example 117: D-SO-Ribofuranuronamido-1-/6-//2-/1-(5-chlorothien-2-yl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/- M-cyclopropyl-1-deoxy-2,3-0-(1-methylztylidene).

Formula (U): Ku - H, n - 1, K» - 5-chlorothien-2-yl, Bz - B. - H,

Co: Y ---MN

I'm SLEEPING

54

Ki Ka r st

Example 118: B-O-Ribofuranuronamido-M-cyclopropyl-1-/6-//2-/1-(cyclopropylmethyl)indol-3-yl/ztyl/amino/-9H-purin-9-yl/-1- deoxy-2,3-0-(1-methylthylidene).

Formula (IM): Ki - H, n - 1, Ko x cyclopropyl, Kz x Ku. - H, 16)

Ko - DI ---MN

SN we m

In V st

The following compounds of examples 119 - 138 were obtained! according to one of the methods of examples 29 or 30.

Example 119: 3-(2-Aminoethyl)-5-chloro-(2,5-dimethylbenzyl) indole.

Formula (1): K, - 5-C1, n - 1, K» - 2,5-dimethylphenyl, Kz - Ku. - N.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 95905 / isopropylamine

Bob).

Example 120: 3-(2-Aminoacetyl)-1-allylindole.

Formula (I): Ki - H, n - 1, V" - ztenil, Kz - Na: N.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 121: 3-(2-Aminoacetyl)-1-(pyrid-2-ylmethyl)-indole.

Formula (1): B "H, n - 1, B" - pyrid-2-yl, Kz - Na: H.

Purified by chromatography on silica gel (solvent: SNCIz 9595 / isopropylamine 595).

Melting point: 23770.

Example 122: 3-(2-Aminoethyl)-5-chloro-(4-chlorobenzyl) indole.

Formula (1): B - 5-CI, n - 1, B" - 4-chlorophenyl, Kz - Na - H.

Hydrochloride, purification and recrystallization from ethanol.

Melting point: 20476.

Example 123: 3-(2-Aminoacetyl)-1-propargylindole.

Formula (1): Vi - H, n - 1, B" - ztynyl, Kz - Na: N.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 124: 3-(2-Aminoethyl)-1-(2,5-dimethylbenzyl)-5-methylindole.

Formula (I): Bi - 5-CHvz, n - 1, A» - 2,5-dimethylphenyl, Kz - Ba - H.

Hydrochloride, purified by crystallization from zinc.

Melting point: 19870.

Example 125: 3-(2-Aminoethyl)-1-(2,5-dimethylbenzyl)-5-methoxyindole.

Formula (I): Bi - 5-OSH», n - 1, Bo - 2,5-dimethylphenyl, Kz - Ba - H.

Amorphous white solid product, purified by chromatography on silica gel (solvent: chloroform 95965 / methanol 5965).

Example 126: 3-(2-Aminoethyl)-1-(2,5-dimethylbenzyl)-2-methylindole

Formula (I): Bi - 2-CHvz, n - 1, A» - 2,5-dimethylphenyl, Kz - Ba - H.

Hydrochloride, purified by chromatography from Zfira.

Melting point: 25070.

Example 127: 3-(2-Aminoacetyl)-1-(4-methoxybenzyl) indole.

Formula (I): A 2 H, n - 1, B» - 4-OSH3-phenyl, Kz - Na: H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 128: 3-(2-Aminoethyl)-1-cyclopentyl-2-methylindole

Formula (1): Vi - 2-CH3, p xx O, Co x cyclopentyl, Kz - Na: H.

Crude orange oil used as such in the next step.

Example 129: 3-(-2-Aminoethyl)-2-phenylindole.

Formula (M): Bi - 2-phenyl, Kz - Na - H.

Hydrochloride, purified by crystallization from isopropanol.

Melting point: 26670.

Example 130: 3-(2-Aminoethyl)-1-(2,5-dimethylbenzyl)-2-phenylindole.

Formula (1): Bi - 2-phenyl, n - 1, H2 - 2,5-dimethylphenyl, Kz - Na: H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 131: 3-(2-Aminoethyl)-1-(2-M,M-dimethylaminobenzyl)indole.

Formula (I): B - H, n - 1, B" - 2-M, M-dimethylaminophenyl, Kz - Ba - H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 132: 3-(2-Aminoacetyl)-1-(3-nitrobenzyl)indole.

Formula (II): Vi - H, n - 1, B» - 3-MO2-phenyl, Kz - Na - H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 133: 3-(2-Aminopropyl)-1-(2,5-dimethylbenzyl)-indole.

Formula (I): Vi - H, n - 1, P» - 2,5-dimethylphenyl, Kz - H, Ka - CHz.

White solid product, purified by crystallization from isopropyl oil.

Melting point: 8770.

Example 134: 3-(2-Aminopropyl)-1-cyclopentylindole.

Formula (I): Ai 2 H, n - 0, B» x cyclopentyl, Kz: H, Na x CH».

Crude orange oil used as such in the next step.

Example 135: 3-Aminopropan-2-yl)-1-(2,5-dimethylbenzyl)indole.

Formula (I): Vi - H, n - 1, P» - 2,5-dimethylphenyl, Kz - CH», Ba - H.

Oil purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine 5905).

The hydrochloride is crystallized from isopropanol.

Zmpirical formula: SgoNgaMeg; NOAH

Melting point: 17870.

Example 136: 3-Aminoethyl)-1-(5-chlorothien-2-yl)methyl/indole.

Formula (I): A: 2 H, n - 1, B" - 5-chlorothien-2-yl, Kz - Na: H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropanol 5905).

Example 137: 3-Aminoethyl)-1-(cyclopropylmethyl)indole.

Formula (II): Vi - H, n - 1, B» - cyclopropyl, Kz - Na: H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Example 138: 3-(2-Aminoethyl)-1-(2,5-dimethylbenzyl)-5-thiomethylindole.

Formula (1): B - 5-52CHvz, n - 1, B2 - 2,5-dimethylphenyl, Ez - Na :- H.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / isopropylamine

Bob).

Nitrovinylindol! examples 139 - 143 were obtained according to the method of example 17:

Example 139: 1-(2,5-Dimethylbenzyl)-2-methyl-3-(2-nitrovinyl)-indole.

Formula (IX): Bi - 2-CH3, n - 1, P» - 2,5-dimethylphenyl, Kz - Ba - H.

Orange oil used as such in the next step.

Melting point: 18070.

Example 140: 1-"Cyclopentyl)-2-methyl-3-(2-nitrovinyl) indole.

Formula (IX): Vi - 2-CH»z, n - 0, Vo - cyclopentyl, Kz - Na - H.

Orange oil purified by chromatography on silica gel (solvent: chloroform).

Example 141: 2-Phenyl-3-(2-nitrovinyl) indole.

Formula (IX): Ni - 2-phenyl, n - 0, B» - H, Ez - Na: H.

Orange oil used as such in the next step.

Melting point: 18070.

Compounds of examples 142 and 143 were prepared according to the method of example 17, using nitrotane instead of nitromethane.

Example 142: 1-(2,5-Dimethylbenzyl)-3-(2-methyl-2-nitrovinyl)indole.

Formula (IX): Vi - H, n - 1, A» - 2,5-dimethylphenyl, Kz - H, Ka - CH».

The yellow solid product crystallizes from water!

Melting point: 16070.

Example 143: 1-Diclopentyl-3-(2-methyl-2-nitrovinyl)-indole

Formula (IX): Ni 2 H, n - 0, B» x cyclopentyl, Kz 2 H, Ka x CHz.

The yellow solid product is crystallized from isopropanol.

Melting point: 13570.

The following product! examples 144 - 146 were obtained according to the method of example 5, based on the corresponding substitutions of C3-formylindols;

Example 144: 1-(2,5-Dimethylbenzyl)-3-formyl-2-methylindole

Formula (MIP): B - 2-CH»z, n - 1, B» - 2,5-dimethylphenyl

The yellow solid product is crystallized from zephyr and used in this form in the next stage.

Melting point: 15570.

Example 145: 1--"Cyclopentyl)-3-formyl-2-methylindole.

Formula (MIP): Vi - 2-CH»z, n - 0, Vo xx cyclopentyl.

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / methanol 595).

Example 146: 3-Formyl-2-phenylindole.

Formula (MIP): B - 2-phenyl, n - 0, A»: H.

A cream-colored solid product, used as such in the next stage and obtained by the method described in U. Mei. Spet., (1964), 7, 735.

Melting point: 25370.

Example 147: B-O-Ribofuranuronamido-1-(6b-chloro-9H-purin-9-yl/-1-deoxy-1M-(2-methoxyethyl)-2,3-0-(1-methylethylidene).

Formula (PI): X «- SI, o

Goats - 6--Fri--snu-snNU Sun,

SN

Viz ra. 4 133 KI growth

Brown oil, purified by chromatography on silica gel (solvent: chloroform 9595 / methanol 5905).

The compound of example 148 was obtained in the form of an amorphous solid product by the method of example 46, using the uronamide of example 2:

Example 148: p-O-Ribofuranuronamido-1-deoxy-1-6-//2-/1-(2,5-dimethyl-benzyl)indol-3-yl/ztyl/amino/-9H-purin-9- yl)-M-zyl-2,3-0-(1-methylztylidene).

Formula (U): K.- H, o, - 1,5-2,5-dimethylphenyl, Kz - K. - H,

Ko - | n her -С-МН-СН. SN, ve us

You are - r 135 114

SYA

The compound of example 149 was obtained by the method of example 61:

Example 149: D-SO-Ribofuranuronamido-1-deoxy-1-6-//2-/1-(2,5-dimethylbenzyl). indol-3-yl/ztyl/amino/-9H-purin-9-yl)-M-ztyl.

Formula (1): A - H, n - 1, A» - 2,5-dimethylphenyl, H3 - H4 - H,

AB - -MH-SNeg-CHz,

Chemical formula: SziNzeM7Ol, 4H2O.

Melting point: 13370.

PHARMACOLOGY

Pharmacological activity of products according to examples was evaluated by two different approaches:

binding to adenosine receptors and/or demonstration of analgesic activity in phenylbenzoquinone test.

Method 1. Binding to adenosine receptors

Principle

The affinity of the products, for example, to the central Ai and Ag adenosinergic receptors is determined by a comparative method using the specific ligand binding of each to Ai receptors (VN/RIA) or to Ag receptors ("H/MESA).

Method. "- Method of obtaining A; receptors - Preparation of tablets

After the animal is killed by decapitation, the brain is quickly removed and washed with a cold isotonic solution. Two hemispheres are separated and weighed, and each is then introduced into a polyallomer test tube containing 25 volumes of cold homogenized buffer. Homogenization is carried out using Shpga-Tiggah for 30 seconds (3 times for 10 seconds with 10-second intervals, 7095 ot of maximum speed). The resulting standard material is centrifuged at 10009 (- 300°C) for 10 minutes at 4"C.

The supernatant is again centrifuged at 480009 (- 20000 grt) for 20 minutes at 4760.

When this stage is completed, the sediment is treated with 4 volumes of homogenizing buffer, resuspended using Moigeh, and homogenized using Shpyga-Titah. Adenosine deaminase is added at a rate of 1 µl/ml, i.e. 1dl/ml homogenate using a 10dl Hamilton syringe.

After processing, the homogenate is shaken for 30 minutes at room temperature and then centrifuged at 800009 (- 20000 grt) for 30 minutes at 470.

The resulting precipitate is resuspended in 10 volumes of homogenizing buffer and passed through OG

Tiigah for 20 seconds (2 times for 10 seconds with 10-second intervals, 7095 at maximum speed).

The homogenate obtained in this way is used in comparative tests. It is stored at 4"C, if the studies are carried out for several days, and for a long time at -20"C in the form of 10ml parts, - Comparative study

After thawing the homogenate at room temperature, it is passed through a Potter's mill (6 hand-operated back and forth, speed 6), diluted 2/5 with incubation buffer and placed in a water bath, thermostatically controlled at 4"C, with shaking until the end of the experiment.

Bonl/ZN/RIA at 100NnM, i.e. 2.5NM in the final reaction medium, allowing to achieve a dilution of 1/40 and for the product according to the example at the considered concentrations (107M and 1077M) are introduced into the reaction tubes.

The reaction is initiated by adding 1 ml of homogenate and 900 dl of incubation buffer. The method is identical for all beta-blockers.

The tubes are shaken and incubated in a water bath at 20"C for 30 minutes. When the incubation is complete, the contents of the tubes are filtered on Whatman SE/V paper. Each tube is washed twice with 2 ml of washing buffer and then filtered and washed with 3 ml of the same buffer.

Filter! then transfer to a counting flask and add 10 ml of liquid scintillator (Keadu 5om HP/B,

VesKtap).

After shaking the flask! keep in the refrigerator all night and then determine the radioactivity in a liquid scintillation counter.

Conducted on 3 opium for each studied concentration. Non-specific binding "N/RIA is estimated by measuring the amount of radioactivity remaining on the filter in the presence of 102M phenylisopropyladenosine (RIA). The amount of non-specific binding is systematically read from the test data. "-" Method of studying Ag receptors - Preparation of membranes

After the animal is killed by decapitation, the brain is quickly removed and washed with a cold isotonic solution. The two hemispheres are separated, and each hemisphere is separated from each other (Vhit5 ei ai., 1986), weighed and introduced into a polyallomer test tube containing 10 volumes of cold homogenized buffer. The tissue is homogenized using ONga-Tiggah for 30 seconds (times of 10 seconds with 10-second intervals, 7095 ot maximum speed). The resulting standard material is centrifuged at 500,009 (- 20,000 grt) for 10 minutes at 426.

The resulting precipitate is re-suspended in 10 volumes of homogenizing buffer using Moigeh, and homogenized using Oiga-Titah (5-10 seconds, 7095 ot of maximum speed).

Adenosine deaminase is added at a rate of 1 µl/ml, i.e. Tdl/ml homogenate using a 100-dl Hamilton syringe. The homogenate obtained in this way is shaken for 30 minutes.

When the incubation is complete, the homogenate is centrifuged at 500,009 (20,500 grt of them) for 10 minutes at 4.

The sediment is treated with 5 volumes of cold homogenizing buffer and passed through ONga-Tiggah (2 times for 10 seconds with 10-second intervals, 7095 at the maximum speed), and the homogenate obtained in this way is finally frozen at -7070. - Comparative study

After thawing the homogenate at room temperature, add 15 volumes of incubation buffer.

The homogenate is shaken on a mop, passed through a Potter's mill (hand-operated back-and-forth, speed 6), diluted 11/10 with incubation buffer and, finally, placed in a water bath thermostated at 4"C, with shaking until the end of the experiment.

Bonl PH/MESA at 160OHnM, i.e. 4NM, in the final reaction medium, allowing to achieve dilution

1/40 and 5 bdl of the product according to the example at the considered concentration (109M and 107M) are introduced into reaction tubes. The reaction is initiated by adding 1 ml of homogenate and 900 dl of incubation buffer. The method is similar for all investigated compounds.

The tubes are shaken and incubated in a water bath at 257°C for 60 minutes. When the incubation is complete, the contents of the tubes are filtered on Whatman CE/V paper. Each tube is washed twice with 2 ml of washing buffer and then filtered and washed with 3 ml of the same buffer before being placed in count the bulb

Add 10 ml of liquid scintillator (Keadu 5om HP/B, WesKktap) to all flasks. They are shaken and kept in the refrigerator all night. Radioactivity is determined in a liquid scintillation counter.

It is carried out on 3 times for each studied concentration. Non-specific binding / "H/MESA is determined by measuring the amount of radioactivity remaining on the filter in the presence of 5NM M- zylcarboxamidoadenosine (MESA). The amount of non-specific binding is systematically read from the test data. "- Data processing

The result! expressed for each product as a percentage of substitution (n - 3) of the released ligand at concentrations of 102M and 1077M. 2. Phenylbenzoquinone study

Method.

Intraperitoneal injection of phenylbenzoquinone suppresses twisting and pulling movements in mice.

Analgesics prevent or reduce this syndrome, which can be considered as an exacerbation or diffusion of abdominal pain. 0.0295 of a solution of phenylbenzoquinone in water is introduced in a volume of 1Tml/100g.

The product according to the examples is administered orally before the injection of phenylbenzoquinone.

Twisting and pulling movements are counted for each muscle during observation for a period of 5 minutes.

II Result

The result! Experiments show the affinity of products for adenosine receptors, and their analgesic properties are presented! in tables 1 and 2, respectively.

Table 1

Product by | due to confusion in the zaltazhny yamgand. in and Ar: in nen ne he s uchu nn nyn tin

OEM O1-MO 0 AM oMm

Examples 01 and ov 4. Shh! 30 and Example 63 SHE: a and c

Example 64. a SHSHCHEYA az ak

Example 05 | 87 4 : m 14 !

For example 08 в 2

Ponmeru 67 what what what.

Example 68 93 Z shk 9

Example 69 93 5 O 1 and ;

Example 70 NO | 9 she; ry.

Example 71 (citrate) mice

TExample 71 (most often: E even for ;

Example 5 I; and Z:

Example 86 6 ate about.

Example 57 With Ge 7 and

Example 93 ШЯ 45 85 g сантвжжс хонни ня жен че не че пеня пена пена 4 lay chee

Table 2

E Product by: phennapbenzoquinonenov neslezhonanne

E E Me nignonruyushaya vine

MK on and Nrimeru 61 | according to "Nrimer i and pon t pi i

Betty" and Example 64! pi 3 o - i Ya

It's about plomaororn von war you vvv vv vnva and Example 65 | 3

Example 66 | With E

For example, there are AIs and them; | | tk and I' of Example 68 | and ! (Example 7 (nirat ! 7 and Ponmeru 55 | to ! and Example yo ! with BO : about Example 87 ! 12 :

Example 92 ШШ ШШ sho ЗB 00000000 rogo tevovvetee no zeeoosoe epoeoteoet spring ooo ovche terte

Example 93 E 2:

AI TtokssykologgIiya

The tolerance of the products is estimated on samples after oral administration. It was found that everything is fine until now! in 100 mg/kg.

KILL THEM

The products according to the examples described in the present invention have particularly valuable analgesic properties, the true mechanism of action of which is the result of interaction with adenosine receptors.

Claims (13)

1. Production of adenosine of the general formula (1): Ez la MH 11 in 6 2 h- M, shi; i (СНо)в В вело в о о о о о о, in which - Vi - is a hydrogen atom, a halogen atom, a lower alkyl radical, a lower O-alkyl radical, a lower 5-alkyl radical or a phenyl radical, and can be in 2-, 4-, 5-, 6- or 7-position indole, - n - is an integer from 0 to 4, - B" - is a lower alkyl radical, lower alkenyl radical, lower alkynyl radical, C3-C7- cycloalkyl radical or lower O-alkyl radical, - phenyl or naphthyl radical, unsubstituted or substituted by one to four identical or different substituents selected from the halogen atom, nitro; lower alkyl, lower O-alkyl or lower 5Z-alkyl group and groups! -MEA?N»a, A; and Hv represent a hydrogen atom or a lower alkyl radical; - a heterocyclic radical, selected from pyridine and thiophene, unsubstituted or substituted by one to four identical or different substituents selected from a halogen atom, nitro, lower alkyl, lower O-alkyl or lower 5-alkyl groups!; - or, in addition, when p equals 2, C or 4, the group -MA»zA:o, No and Naio are simultaneously lower alkyl radicals or together with the nitrogen atom to which they are attached form a heterocycle selected from morpholine, piperidine and pyrrolidine; - Vz and Ba, which are the same or different, are a hydrogen atom or a lower alkyl radical; and - B5 - so the group -MNN and, Vii is a lower alkyl radical, a C3-C7-cycloalkyl radical or a lower alkyl chain possessing an alcohol or sulfur functional group, or, in addition, the group -(CHg)p- MAR»no, n, No and But how to define more. 2. Derivation of general formulas! (I) according to claim 1, where - Vi is a hydrogen atom, a halogen atom, a lower alkyl radical, a lower O-alkyl radical, a lower 5-alkyl radical or a phenyl radical, and can be in the 2- or 5-position of indole; - n is an integer equal to 0, 1 or 2; - B" means a lower alkyl radical, a lower alkenyl radical, a lower alkynyl radical, a C3-C7-cycloalkyl radical or a lower O-alkyl radical, - a phenyl or naphthyl radical, unsubstituted or substituted by one to two identical or different substituents selected from halogen atom, nitro; lower alkyl or lower O-alkyl groups and groups -МА7Ав, А? and Az are hydrogen atoms or lower alkyl radicals; - a heterocyclic radical derived from pyridine and thiophene, unsubstituted or substituted by a halogen atom; - or, in addition, when n - 2, the group -MA»Ao, Ne and Nio simultaneously represent a lower alkyl radical or together with the nitrogen atom to which they are attached form a heterocycle selected from morpholine, piperidine and pyrrolidine; - Bz and Ba, which are the same or different, are a hydrogen atom or a lower alkyl radical, and Av is a group -МННА and, Vi is a lower alkyl radical, a C3-C7-cycloalkyl radical or a lower alkyl chain possessing an alcohol or sulfur functional group . 3. Derivative according to claim 1 or claim 2, characterized by the fact that Ri is a hydrogen atom or a radical selected from methyl or methoxy. 4. The derivative according to claim 1 or claim 2, characterized by the fact that n is an integer equal to 0, 1 or 2. 5. Derivative according to claim 1 or claim 2, characterized by the fact that No is a radical selected from methoxy, cyclopentane, isopropyl, 2,5-dimethylphenyl and piperidine. 6. Derivative according to claim 1 or claim 2, characterized by the fact that Hz is a hydrogen atom. 7. Derivative according to claim 1 or claim 2, characterized by the fact that Bl is a hydrogen atom or a metal radical. 8. Derivative according to claim 1 or claim 2, characterized by the fact that H5 is an M-cyclopropylamine radical. 9. A derivative according to claim 1 or claim 2, distinguished by the fact that it is selected from the following derivatives: What is in and: I. 4 o'clock "Su Fo sn - and I and not st; Fo | with i and Mn Sta y Y Fe u shch SNu M M on on MN Fshe M Her SF U o -- o g; he she"- 10. The method for obtaining compounds of formulas (I) according to any of claims 1-9, characterized by the fact that it includes the interaction of an amine of the formula VZ Ki and MN Kk Y ' sho Ko in which Vi, R», Vz, Va and p as defined in claim 1 or claim 2, with b-halopurine riboside of the formulas! Хх M her мм / К?2 о КизО 0 An eye in which X is a halogen atom, Ві" is a group СОН», Н5, as defined in claim 1 or claim 2, or a group СНеОН, and Віз and Ві" are protected groups, such as, for example, acetyl, benzoyl or benzyl, or can together form another protecting group, for example, a dioxolane structure, in a solvent such as alcohol or dimethylformamide, in the presence of a base such as trisethylamine, pyridine or sodium carbonate, potassium or calcium, or, in addition, in the presence of two equivalents of amine at a temperature between 20"7С and 1402С, after which the protective groups are removed from alcohols by various known methods, known to specialists, namely, in a basic medium with an ammonium hydroxide solution, or in an acidic medium with a normal solution of hydrochloric acid or formic acid at a temperature from 0"C to 70"C, depending on the nature of the protective groups. 11. Pharmaceutical composition, characterized by the fact that it contains a pharmaceutically effective amount of at least one compound of formulas (I), defined in any of claims 1-9, or one of its pharmaceutically acceptable salts, which may or may not be combined with pharmaceutically acceptable additive, solvent or carrier. 12. A method of obtaining a pharmaceutical composition, characterized by the fact that it includes mixing a pharmaceutically effective amount of at least one compound of the formulas! (I) defined in any of claims 1-9, or one of its pharmaceutically acceptable salts to a pharmaceutically acceptable additive, solvent or carrier. 13. The method according to claim 12, characterized by the fact that the pharmaceutical composition is used in the form of gelatin capsules or tablets containing from 5 to 300 mg of the active ingredient, or as preparations for injections containing from 0.1 to 100 mg of the active ingredient.